Adel Driss

Genetic polymorphisms linked to susceptibility to malaria

The influence of host genetics on susceptibility to Plasmodium falciparum malaria has been extensively studied over the past twenty years. It is now clear that malaria parasites have imposed strong selective forces on the human genome in endemic regions. Different genes have been identified that are associated with different malaria related phenotypes. Factors that promote severity of malaria include parasitaemia, parasite induced inflammation, anaemia and sequestration of parasitized erythrocytes in brain microvasculature.Recent advances in human genome research technologies such as genome-wide association studies (GWAS) and fine genotyping tools have enabled the discovery of several genetic polymorphisms and biomarkers that warrant further study in host-parasite interactions. This review describes and discusses human gene polymorphisms identified thus far that have been shown to be associated with susceptibility or resistance to P. falciparum malaria. Although some polymorphisms play significant roles in susceptibility to malaria, several findings are inconclusive and contradictory and must be considered with caution. The discovery of genetic markers associated with different malaria phenotypes will help elucidate the pathophysiology of malaria and enable development of interventions or cures. Diversity in human populations as well as environmental effects can influence the clinical heterogeneity of malaria, thus warranting further investigations with a goal of developing new interventions, therapies and better management against malaria.

Sickle Cell Disease in the Post Genomic Era: A Monogenic Disease with a Polygenic Phenotype

More than half a century after the discovery of the molecular basis of Sickle Cell Disease (SCD), the causes of the phenotypic heterogeneity of the disease remain unclear. This heterogeneity manifests with different clinical outcomes such as stroke, vaso-occlusive episodes, acute chest syndrome, avascular necrosis, leg ulcers, priapism and retinopathy. These outcomes cannot be explained by the single mutation in the beta-globin gene alone but may be attributed to genetic modifiers and environmental effects. Recent advances in the post human genome sequence era have opened the door for the identification of novel genetic modifiers in SCD. Studies are showing that phenotypes of SCD seem to be modulated by polymorphisms in genes that are involved in inflammation, cell–cell interaction and modulators of oxidant injury and nitric oxide biology. The discovery of genes implicated in different phenotypes will help understanding of the physiopathology of the disease and aid in establishing targeted cures. However, caution is needed in asserting that genetic modifiers are the cause of all SCD phenotypes, because there are other factors such as genetic background of the population, environmental components, socio-economics and psychology that can play significant roles in the clinical heterogeneity.

PDGF Upregulates Mcl-1 Through Activation of β-Catenin and HIF-1α-Dependent Signaling in Human Prostate Cancer Cells

Background Aberrant platelet derived growth factor (PDGF) signaling has been associated with prostate cancer (PCa) progression. However, its role in the regulation of PCa cell growth and survival has not been well characterized. Methodology/Principal Findings Using experimental models that closely mimic clinical pathophysiology of PCa progression, we demonstrated that PDGF is a survival factor in PCa cells through upregulation of myeloid cell leukemia-1 (Mcl-1). PDGF treatment induced rapid nuclear translocation of β-catenin, presumably mediated by c-Abl and p68 signaling. Intriguingly, PDGF promoted formation of a nuclear transcriptional complex consisting of β-catenin and hypoxia-inducible factor (HIF)-1α, and its binding to Mcl-1 promoter. Deletion of a putative hypoxia response element (HRE) within the Mcl-1 promoter attenuated PDGF effects on Mcl-1 expression. Blockade of PDGF receptor (PDGFR) signaling with a pharmacological inhibitor AG-17 abrogated PDGF induction of Mcl-1, and induced apoptosis in metastatic PCa cells. Conclusions/Significance Our study elucidated a crucial survival mechanism in PCa cells, indicating that interruption of the PDGF-Mcl-1 survival signal may provide a novel strategy for treating PCa metastasis.

CXCL10 Gene Promoter Polymorphism -1447A>G Correlates with Plasma CXCL10 Levels and is Associated with Male Susceptibility to Cerebral Malaria

The risk factors for cerebral malaria (CM) and the wide variation in clinical manifestations of malaria are poorly understood. Recent studies indicate that interferon gamma inducible chemokine, CXCL10, is a strong predictor of both human and experimental cerebral malaria. Increased plasma and cerebrospinal fluid levels of CXCL10 were tightly associated with fatal CM in Indian and Ghanaian patients. In the present study, we hypothesized that in a subset of malaria patients, CM susceptibility is associated with variation in CXCL10 expression. We determined whether polymorphisms in the CXCL10 gene promoter region played a role in the clinical status of malaria patients and addressed the genetic basis of CXCL10 expression during malaria infection. Following extensive bioinformatics analyses, two reported single nucleotide polymorphisms in the CXCL10 promoter (−135G>A [rs56061981] and −1447A>G [rs4508917]) were identified among 66 CM and 69 non-CM Indian patients using PCR-restriction fragment length polymorphism assay. Individuals with the −1447(A/G) genotype were susceptible to CM (adjusted odds ratio [AOR] = 2.60, 95% CI = 1.51–5.85, p = 0.021). In addition, individuals with the −1447(A/G) genotype had significantly higher plasma CXCL10 levels than individuals with the −1447(A/A) genotype. Stratifying patients according to gender, the observed association of CM with over expression of CXCL10 were more pronounced in males than in female patients (AOR = 5.47, 95% CI = 1.34–22.29, p = 0.018). Furthermore, −135G>A polymorphism conferred a decreased risk of CM among males (AOR = 0.19, 95% CI = 0.05–0.78, p = 0.021). Polymorphisms in the CXCL10 gene promoter sequence were associated with increased CXCL10 production, which is linked to severity of CM. These results suggest that the −1447A>G polymorphism in CXCL10 gene promoter could be partly responsible for the reported variation underlying severity of CM outcomes particularly in males.

Plasma interleukin-1β concentration is associated with stroke in sickle cell disease

The pathogenesis of sickle cell disease (HbSS), which has numerous complications including stroke, involves inflammation resulting in alteration of plasma inflammatory protein concentration. We investigated HbSS children with abnormal cerebral blood flow detected by trans-cranial Doppler ultrasound (TCD) who participated in the multi-center stroke prevention (STOP) study, to determine if plasma inflammatory protein concentration is associated with the outcome of stroke. Thirty-nine plasma samples from HbSS participants with elevated TCD who had no stroke, HbSS-NS (n=13) or had stroke, HbSS-S (n=13), HbSS steady-state controls (n=7) and controls with normal hemoglobin, HbAA (n=6), were analyzed simultaneously for 27 circulating inflammatory proteins. Logistic regression and receiver operating characteristics curve analysis of stroke on plasma inflammatory mediator concentration, adjusted for age and gender, demonstrated that interleukin-1beta (IL-1beta) was protective against stroke development (HbSS-NS=19, 17-23, HbSS-S=17, 16-19 pg/mL, median and 25th-75th percentile; odds ratio=0.59, C.I.=0.36-0.96) and was a good predictor of stroke (area under curve=0.852). This result demonstrates a strong association of systemic inflammation with stroke development in HbSS via moderately increased plasma IL-1beta concentration, which is furthermore associated with a decreased likelihood of stroke in HbSS.

Pregnancy outcomes among patients with sickle cell disease at Korle-Bu Teaching Hospital, Accra, Ghana: retrospective cohort study.

Pregnancy in sickle cell disease (SCD) patients is associated with increased risk of maternal and fetal mortality. This study determines pregnancy outcomes among women with SCD delivering at Korle-Bu Teaching Hospital, Accra, Ghana. Nine hundred sixty (960) medical records of pregnant women (131 HbSS, 112 HbSC, and 717 comparison group) from 2007 to 2008 were reviewed. The HbSS women were at increased risk of eclampsia (adjusted odds ratio [AOR] = 10.56, 95% confidence interval [CI] = 3.60-30.96, P < 0.001), intrauterine growth restriction (AOR = 4.00, 95% CI = 1.38-11.64, P = 0.011), and placenta previa (AOR = 22.03, 95% CI = 9.87-49.14, P < 0.001) compared with the comparison group. The HbSC women had increased risk for intrauterine fetal death (AOR = 3.38, 95% CI = 1.15-9.96, P = 0.027) and decreased risk of delivering low birth weight babies (AOR = 0.21, 95% CI = 0.06-0.73, P = 0.014). Women with SCD in Ghana are at a greater risk of morbidity and mortality in pregnancy compared with women without hemoglobinopathies. Improved maternal and fetal outcomes in Ghanaian women with SCD can be achieved through effective intervention by health care providers with thorough knowledge about predisposing factors toward adverse outcomes.

Exosomes derived from endometriotic stromal cells have enhanced angiogenic effects in vitro

Our objective has been to establish a pro-angiogenic role for exosomes in endometriosis and to determine whether a differential expression profile of cellular and exosomal microRNAs (miRNAs) exists in endometriosis. We performed an in vitro study of human primary endometrial stromal cells (ESCs) and human umbilical vein endothelial cells (HUVECs). We isolated and characterized exosomes from ESCs from five endometriosis patients and five phase-matched controls. Exosomes were characterized by transmission electron microscopy and NanoSight technology. MiRNA was assessed by deep sequencing and reverse transcription with quantitative polymerase chain reaction. Exosome uptake studies were achieved by means of confocal microscopy. The pro-angiogenic experiments were executed by treating HUVECs with ESC-derived exosomes. We observed differential profiles of exosomal miRNA expression between exosomes derived from endometriosis lesion cells and diseased eutopic stromal cells compared with exosomes derived from control ESCs. We also demonstrated autocrine cellular uptake of exosomes and paracrine functional angiogenic effects of exosomes on HUVECs. The results of this study support the hypothesis that exosomes derived from ESCs play autocrine/paracrine roles in the development of endometriosis, potentially modulating angiogenesis. The broader clinical implications are that Sampson’s theory of retrograde menstruation possibly encompasses the finding that exosomes work as intercellular communication modulators in endometriosis.

Heme-Mediated Induction of CXCL10 and Depletion of CD34+ Progenitor Cells Is Toll-Like Receptor 4 Dependent.

Plasmodium falciparum infection can cause microvascular dysfunction, cerebral encephalopathy and death if untreated. We have previously shown that high concentrations of free heme, and C-X-C motif chemokine 10 (CXCL10) in sera of malaria patients induce apoptosis in microvascular endothelial and neuronal cells contributing to vascular dysfunction, blood-brain barrier (BBB) damage and mortality. Endothelial progenitor cells (EPC) are microvascular endothelial cell precursors partly responsible for repair and regeneration of damaged BBB endothelium. Studies have shown that EPC’s are depleted in severe malaria patients, but the mechanisms mediating this phenomenon are unknown. Toll-like receptors recognize a wide variety of pathogen-associated molecular patterns generated by pathogens such as bacteria and parasites. We tested the hypothesis that EPC depletion during malaria pathogenesis is a function of heme-induced apoptosis mediated by CXCL10 induction and toll-like receptor (TLR) activation. Heme and CXCL10 concentrations in plasma obtained from malaria patients were elevated compared with non-malaria subjects. EPC numbers were significantly decreased in malaria patients (P < 0.02) and TLR4 expression was significantly elevated in vivo. These findings were confirmed in EPC precursors in vitro; where it was determined that heme-induced apoptosis and CXCL10 expression was TLR4-mediated. We conclude that increased serum heme mediates depletion of EPC during malaria pathogenesis.

Elevated IL-1α and CXCL10 serum levels occur in patients with homozygous sickle cell disease and a history of acute splenic sequestration.

Acute splenic sequestration (ASS) and chronic hypersplenism are common features of homozygous sickle cell (SS) disease in the first 5 years of life affecting one-third of subjects in the Jamaican Cohort Study. The risk factors are largely unknown and the current study explores a possible role of genetic factors. We have explored these in subjects who received splenectomy in the management of ASS (n=8) or chronic hypersplenism (n=9) along with age, gender, and genotype matched controls using Luminex Technology to assess 42 human cytokines/chemokines, including IL-1α and CXCL10 (IP-10). Levels of IL-1α (p=0.008) and CXCL10 (p=0.009) were significantly elevated in patients treated by splenectomy compared with the control group. Levels of IL-1α were significantly higher in those with a history of ASS compared with matched normal controls (p=0.028) but not in those treated for hypersplenism (p=0.093). Furthermore, several significant differences were found in the median ratios of some cytokine biomarkers between the splenectomized group and the normal controls. These observations are consistent with acute splenic sequestration having a distinct phenotype which may be helpful in predicting those at risk of this complication and suggest that the mechanism of these differences merit further study.

Curcumin attenuates proangiogenic and proinflammatory factors in human eutopic endometrial stromal cells through the NF-κB signaling pathway: CHOWDHURY et al.

Endometriosis is a chronic gynecological inflammatory disorder in which immune system dysregulation is thought to play a role in its initiation and progression. Due to altered sex steroid receptor concentrations and other signaling defects, eutopic endometriotic tissues have an attenuated response to progesterone. This progesterone‐resistance contributes to lesion survival, proliferation, pain, and infertility. The current agency‐approved hormonal therapies, including synthetic progestins, GnRH agonists, and danazol are often of limited efficacy and counterproductive to fertility and cause systemic side effects due to suppression of endogenous steroid hormone levels. In the current study, we examined the effects of curcumin (CUR, diferuloylmethane), which has long been used as an anti‐inflammatory folk medicine in Asian countries for this condition. The basal levels of proinflammatory and proangiogenic chemokines and cytokines expression were higher in primary cultures of stromal cells derived from eutopic endometrium of endometriosis (EESC) subjects compared with normal endometrial stromal cells (NESC). The treatment of EESC and NESC with CUR significantly and dose‐dependently reduced chemokine and cytokine secretion over the time course. Notably, CUR treatment significantly decreased phosphorylation of the IKKα/β, NF‐κB, STAT3, and JNK signaling pathways under these experimental conditions. Taken together, our findings suggest that CUR has therapeutic potential to abrogate aberrant activation of chemokines and cytokines, and IKKα/β, NF‐κB, STAT3, and JNK signaling pathways to reduce inflammation associated with endometriosis.